Antifungal drugs

Ghanshyam pd. sah

17th batch ,intern
1. Antifungal drugs are used for the treatment of fungal

infections (mycoses) that may be superficial or deep

infections.

2. Fungal infections are susceptible to the

immunocompromised patients due to chemotherapy or

antibiotic use.
 Classification of antifungal drugs
1.Antibiotics
a.polyenes:Amphotericin B,Nystatin,Hamycin
b.Heterocyclic benzofuran:Griseofulvin
2.Antimetabolite:flucytosine
3.Azoles
a.Imidazoles
i.Topical:Clotrimazole,Eeconazole,Miconazole,
Oxiconazole
ii.systemic:ketoconazole
b.Triazoles(systemic):Fluconazole,Itraconazole,
Voriconazole
4.Allylamine:Terbinafine
5.Other topical agents:
Tolnaftate,Benzoic acid,Undecylenic acid,Butenafine
 Amphotericin B

•Amphotericin A & B are antifungal antibiotics,

Amphotericin A is not used clinically.

Pharmokinetics of Amphotericin
B
•Poorly absorbed orally , is effective for fungal infection of

gastrointestinal tract.

•For systemic infections given as slow I.V.I.

•Metabolized in liver

•Excreted slowly in urine over a period ofseveral days.

•Half-life 16 days.
Mechanism of action of
Amphotericin B

• It is a selective fungicidal drug.

• Disrupt fungal cell membrane by binding to ergosterol , so alters

the permeability of the cell membrane leading to leakage of

intracellular ions & macromolecules (cell death )

Resistance to amphotericin B

• If ergosterol binding is impaired either by :

• Decreasing the membrane concentration of

ergosterol.

• Or by modifying the sterol target molecule.

 Adverse effects OF
AmphotericinB
1- Immediate reactions(Infusion –related toxicity).

Fever, muscle spasm, vomiting, headache, hypotension.

• Can be avoided by:

A. Slowing the infusion

B. Decreasing the daily dose

C.Premedication with antipyretics, antihistamincs orcorticosteroids.

D. A test dose
2- Slower toxicity

• Most serious is renal toxicity (nearly in all patients ).

• Hypokalemia

• Hypomagnesaemia

• Impaired liver functions

• Thrombocytopenia

• Anemia
Clinical use OF Amphotericin B

• Has a broad spectrum of activity & fungicidal action.

• The drug of choice for life-threatening mycotic infections.

• For induction regimen for serious fungal infection.

• Also, for chronic therapy & preventive therapy of relapse.

• In cancer patients with neutropenia who remain febrile on broad –

spectrum antibiotics
Nystatin

• similar in structure & mechanism to amphotericin B.

• Too toxic for systemic use.

• Used only topically.

• It is available as creams, ointments,and other preparations.

• Not significantly absorbed from skin, mucous membrane, GIT .

Clinical use of Nystatin

• Prevent or treat superficial candidiasis of mouth,

esophagus, intestinal tract.

• Vaginal candidiasis

• Can be used in combination with antibacterial

agents & corticosteroids.

Azoles

• A group of synthetic fungistatic agents with a broad

spectrum of activity .

• They have antibacterial , antiprotozoal

anthelminthic & antifungal activity

Mechanism of action of Azoles

1-Inhibit the fungal cytochrome P450 enzyme, (α-demethylase)

which is responsible for converting lanosterol to ergosterol ( the

main sterol in fungal cell membrane ).

2- Inhibition of mitochondrial cytochrome oxidase leading to

accumulation of peroxides that cause autodigestion of the fungus.

3- Imidazoles may alter RNA& DNA metabolism

Azoles

• They are classified into :

• Imidazole group

• Triazole group
Imidazoles

• Ketoconazole

• Miconazole

• Clotrimazole

• They lack selectivity ,they inhibit human gonadal and steroid

synthesis leading todecrease testosterone & cortisol production.

• Also, inhibit human P-450 hepatic enzyme.

Ketoconazoles

• Well absorbed orally .

• Bioavailability is decreased with antacids, H2blockers , proton

pump inhibitors & food .

• Cola drinks improve absorption in patients with achlorhydria.

• Half-life increases with the dose , it is (7-8 hrs)

Clinical uses of ketoconazole

• Used topically or systematic (oral route only ) to treat :

1- Oral & vaginal candidiasis.

2- Dermatophytosis.

3- Systemic mycoses
Adverse effects of ketoconazole
• Nausea, vomiting ,anorexia

• Hepatotoxic

• Inhibits human P 450 enzymes

• Inhibits adrenal & gonadal steroids leading to:

• Menstrual irregularities

• Loss of libido

• Impotence

• Gynaecomastia in males
Contraindication of ketoconazole

•Pregnancy, lactation ,hepatic dysfunction

• Interact with enzyme inhibitors , enzyme inducers.

• H2 blockers & antacids decrease its absorption

Triazoles

• Fluconazole

• Itraconazole

• Voriconazole

• They are :

• Selective

• Resistant to degradation

• Causing less endocrine disturbance

Fluconazole

• Bioavailability is not affected by food or

• gastric PH

Clinical uses

• Candidiasis ( is effective in all forms of mucocutaneous candidiasis)

• Cryptococcus meningitis

• Histoplasmosis, blastomycosis, , ring worm

Side effects of fluconazole

• Nausea, vomiting, headache, skin rash ,

• diarrhea, abdominal pain , reversible alopecia.

• Hepatic failure may lead to death

• Highly teratogenic ( as other azoles)

Flucytosine

• Synthetic pyrimidine antimetabolite (cytotoxic drug ) often given in

combination with amphotericin B & itraconazole.

• Systemic fungistatic ,rapid and well absorbed orally

Mechanism of action

• Converted within the fungal cell to 5-fluorouracil (Not in human

cell ), that inhibits thymidylate synthetase enzyme that inhibits DNA
synthesis
Clinical uses of Flucytosine

• Severe deep fungal infections as in meningitis

• Generally given with amphotericin B

• For cryptococcal meningitis in AIDS patients

Adverse effects
• Nausea, vomiting , diarrhea, severe enterocolitis
• Reversible neutropenia, thrombocytopenia,
• bone marrow depression
• Alopecia
 Griseofulvin

• Fungistatic, has a narrow spectrum

• Given orally (Absorption increases with fatty meal )

• Taken selectively by newly formed skin & concentrated in the

keratin.

• Should be given for 2-6weeks for skin & hair infections to

allow replacement of infected keratin by the resistant
structure
Mechanism of actions of
Griseofulvin
• Inhibits fungal mitosis by interfering with microtubule function

Uses of griseofulvin
•Used to treat dermatophyte infections ( ring worm of skin, hair,
nails ).
• Highly effective in athlete foot

Adverse effects
• Peripheral neuritis, mental confusion, fatigue, vertigo,
• GIT upset, enzyme inducer, blurred vision.
• Increases alcohol intoxication.
Terbinafine
• Drug of choice for treating dermatophytes (onychomycoses)
• Effective for treatment of onychomycoses
• 6 weeks for finger nail infection & 12 weeks for toe nail infections .

side effects

• Severely hepatotoxic, liver failure even death.

• Accumulate in breast milk , should not be given to nursing mother.
• GIT upset (diarrhea, dyspepsia, nausea )
• Taste & visual disturbance.
 References
.ESSENTIALS OF MEDICAL PHARMACOLOGY
KD TRIPATHI EIGHTH EDITION
.GOOGLE

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